Prostate cancer is the most prevalent malignancy in men, responsible for more than 33,000 deaths in 2011. However, most prostate cancers have a relatively slow rate of growth and progression and are ideal candidates for non-toxic pharmacological or nutritional interventions that could reduce the incidence of clinically relevant disease, delay cancer progression, and modify a malignant process into a chronic, manageable disease. The central hypothesis of this grant application is that vitamin D3 supplementation will benefit Veteran subjects diagnosed with early-stage, low-risk prostate cancer, who elect to have their disease managed through active surveillance. Specifically, we hypothesize that Veterans who take 4000 international units (IU) of vitamin D3 per day (intervention group) will show an improvement in the number of positive cores and in Gleason score at repeat biopsy, and a decreased likelihood of undergoing definitive treatment (prostatectomy or radiation therapy), compared to Veteran subjects taking placebo (control group). To test this hypothesis, we propose the following Specific Aims: 1) To determine whether vitamin D3 (4,000 IU per day for at least one year) will result in a significant improvement of the pathology status at repeat biopsy in Veteran subjects taking vitamin D3, compared to Veteran subjects taking placebo. This hypothesis will be tested through a randomized clinical trial, which will enroll 136 Veteran subjects (68 participants per arm), diagnosed with low-risk prostate cancer (Gleason score d6, PSA d10, clinical stage T1C or T2a). The pathology status will be measured by the change in Gleason score and the number of positive cores in prostate needle biopsy specimens between baseline and the end of the study. Pre- and post-study biopsies will be performed as part of the standard medical care for active surveillance. 2) To determine whether vitamin D3 supplementation, compared to placebo, will result in a significant decrease in the number of Veteran subjects who will undergo definitive treatment (prostatectomy or radiation therapy), following the outcome of repeat biopsy. 3) To analyze changes in the serum levels of cholecalciferol, 25(OH)D, 1,25(OH)2D, and prostate-specific antigen (PSA) at baseline and at the end of the study, and to estimate the associations between changes in these measures and pathology outcomes. 4) To compare the expression of molecular biomarkers, which are prognostically relevant to prostate cancer progression, in pre- and post-treatment biopsy tissue specimens. Paraffin- embedded sections will be processed to assess by immunohistochemical techniques the expression of the following biomarkers: vitamin D receptor (VDR), p21, tumor growth factor beta (TGFbeta), cyclooxygenase 2 (COX- 2), and NFkappaB. All of these protein products impact growth control and chronic inflammation in prostate cancer progression and are specifically affected by vitamin D status. Vitamin D3 supplementation may not only provide a welcome addition to active surveillance, but also help us avoid over treating low-risk disease in subjects who respond to an intervention strategy that is extremely cost-effective and easy to implement. At the same time, Vitamin D3 supplementation would help us identify those patients (non-responders) who are affected by potentially aggressive disease and should consider definitive treatment.